Pseudo-pheochromocytoma due to obstructive sleep apnea: a case report.

A 65-year-old male patient initially presented to endocrinology in February 2010 for assessment of a 2.9-cm left adrenal incidentaloma that was found on CT abdomen that was done for right upper quadrant pain and cholelithiasis ( Fig. 1 ). The Hounsfield units ranged from −7 to 17. He reported a several month history of increased headaches, nocturnal diaphoresis, and increased anxiety. His initial blood pressure in the office was elevated at 160/98 mmHg with no prior history of hypertension. Figure 1 Left adrenal incidentaloma noted on enhanced CT. The mass was a well-circumscribed hypodense left adrenal nodule measuring 2.9 cm. The Hounsfield units ranged from −7 to 17. Pathological analysis following left adrenalectomy demonstrated an adrenal cortical adenoma with negative immunohistochemical staining for pheochromocytoma. Left adrenal incidentaloma noted on enhanced CT. The mass was a well-circumscribed hypodense left adrenal nodule measuring 2.9 cm. The Hounsfield units ranged from −7 to 17. Pathological analysis following left adrenalectomy demonstrated an adrenal cortical adenoma with negative immunohistochemical staining for pheochromocytoma.

A J, S H P, and M P drafted the manuscript and approved the final version. S H P and M P were directly involved in the patient’s care.

This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

In May 2012, he was diagnosed as having OSA and was initiated on treatment with nocturnal continuous positive airway pressure (CPAP). After his OSA was treated, repeat urine testing showed complete normalization of urine norepinephrine and metanephrines with substantial symptom improvement ( Table 2 ). Table 2 24-h urine catecholamine and metanephrine results after OSA treatment. The patient underwent a left adrenalectomy in July 2010. Date Jan 2017 March 3, 2017* March 28, 2017 N Range Metanephrine 0.04 0.08 0.04 <0.20 µmol/day Normetanephrine 0.45 0.70 0.37 <0.20 µmol/day Epinephrine 26 39 19 <90 nmol/day Norepinephrine 396 774 422 <650 nmol/day Dopamine 2676 3715 1389 400-3300 nmol/day Creatinine 19.5 35.8 14.3 7-18 nmol/day *Probable over collection of urine. Bold values represent lab results outside the normal limits. 24-h urine catecholamine and metanephrine results after OSA treatment. The patient underwent a left adrenalectomy in July 2010. *Probable over collection of urine. Bold values represent lab results outside the normal limits. It was concluded that the patient never had a pheochromocytoma and that he had a non-functioning adrenal adenoma with biochemistry and symptoms suggestive of pheochromocytoma due to untreated severe OSA, which resolved with CPAP therapy.

Written informed consent has been obtained from the patient for publication of the submitted article. This has been documented in the patient’s medical records.

Given his symptoms, imaging, and investigations, he was diagnosed with a pheochromocytoma, started on alpha-blockade with prazosin, and referred for surgery. His prazosin was slowly titrated to 2 mg twice-a-day preoperatively, and he had a left adrenalectomy in July 2010. Pathology revealed an adrenal corticoadenoma with no evidence of pheochromocytoma. There was a persistent and significant elevation in his 24-h urine norepinephrine and normetanephrine over the next 2 years ( Table 1 ). Given his negative pathology, a paraganglioma was suspected. However, there was no evidence of an extra-adrenal source, with three MIBG scans showing no evidence of MIBG avid disease and normal CT scans of the head, spine, chest, and abdomen. His blood pressure improved without initiation of antihypertensives, but he continued to have persistent headaches, anxiety, and diaphoresis.

Adrenal incidentalomas are a common finding in patients undergoing abdominal and pelvic CT scans and require functional assessment once identified. Pheochromocytoma is diagnosed in 5% of functional adrenal incidentalomas and must be excluded given its high morbidity and mortality ( 1 , 2 ). Pheochromocytomas and paragangliomas are catecholamine-secreting tumors derived from the adrenal medulla and nerve cell paraganglia, respectively ( 3 ). Classical symptoms include headache, palpitations, diaphoresis, hypertension, and pallor. Life-threatening complications including hypertensive crisis, catecholamine-induced cardiomyopathy, and multi-organ dysfunction may occur due to prolonged catecholamine release. Diagnosis can be challenging, as clinical symptoms vary and localization of the catecholamine-secreting tumor may be difficult. Diagnosis is made based on elevated catecholamines and metanephrines in conjunction with localization studies. Laparoscopic adrenalectomy is the mainstay of treatment for pheochromocytoma ( 4 ). Pseudo-pheochromocytoma is a disorder that presents similarly to pheochromocytoma with paroxysmal hypertension, palpitations, diaphoresis, and chest pain ( 5 ). However, unlike pheochromocytomas and paragangliomas, pseudo-pheochromocytomas present in the absence of catecholamine-secreting tumors. Pseudo-pheochromocytoma is a diagnosis of exclusion, and commonly associated conditions include obstructive sleep apnea (OSA), physiologic stress, antipsychotic drugs, anti-Parkinson drugs, tricyclic antidepressants, and cocaine use.

OSA is a common condition that affects up to 9–38% of adults ( 6 ). It is diagnosed based on overnight oximetry testing or with polysomnography. Recurrent hypoxia with repeated sudden arousal triggers a surge of sympathetic nervous activity which can result in elevated urine catecholamines and metanephrines and a clinical picture of pheochromocytoma ( 7 , 8 ). OSA is a known risk factor for cardiovascular disease, stroke, and hypertension. This risk may be due to the elevated catecholamines and metanephrines from recurrent hypoxia. Treatment is with CPAP, which decreases sympathetic tone by preventing upper airway closure and stopping recurrent hypoxia ( 9 ). OSA rarely presents as a pseudo-pheochromocytoma with elevated catecholamines and metanephrines along with symptoms of pallor, palpitations, perspiration, headache or anxiety, and has only been documented in case reports. Similar to our case, previous reports note resolution of clinical symptoms and normalization of catecholamines and metanephrines with proper treatment of OSA with CPAP ( 7 ). When a patient presents with suspicion for pheochromocytoma but imaging does not identify a mass, a pseudo-pheochromocytoma should be considered. If an adrenal mass is present, biochemical features may be used to support the diagnosis of pheochromocytoma. Elevations in both metanephrine and normetanephrine levels are most consistent with adrenal localization ( 10 ). Isolated normetanephrine elevation without metanephrine elevation, as in our case, may point away from a diagnosis of pheochromocytoma, but adrenal or extra-adrenal localization with likely VHL or SDHx mutations still needs to be considered ( 10 ). In addition to OSA, physiologic stress, antipsychotic drugs, anti-Parkinson drugs, tricyclic antidepressants, and cocaine use are on the differential diagnosis of a pseudo-pheochromocytoma ( 5 ). It is important to properly diagnose pseudo-pheochromocytoma due to OSA to avoid unnecessary surgery along with its potential risks and to decrease the associated comorbidities of OSA. Appropriate treatment of OSA with CPAP should normalize urinary catecholamines and metanephrines and help resolve associated symptoms in the setting of OSA-associated pseudo-pheochromocytoma.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

His endocrine workup revealed elevated 24-h urine norepinephrine of 818 nmol/day (89–470) and normetanephrine of 11.2 µmol/day (0.6–2.7), and repeat testing showed persistent elevation in normetanephrines at 9.9 nmol/day (0.6–2.7) ( Table 1 ). Measurements of urine norepinephrine and normetanephrine were completed using high-performance liquid chromatography and electrochemical detection. He was on no interfering medications at that time. Given the adrenal incidentaloma, workup for primary hypoaldosteronism and Cushing’s syndrome was done, with normal 24-h urine aldosterone and 24-h urinary free cortisol. Table 1 24-h urine catecholamine and metanephrine results prior to OSA treatment. The patient underwent a left adrenalectomy in July 2010. Date May 2010 June 2010 Aug 2010 Aug 2011* April 2012** April 2012*** Oct 2012 Dec 2013 N Range Metanephrine 0.5 0.5 <0.4 <0.4 0.23 0.4 <0.4 <0.20 µmol/day Normetanephrine 11.2 9.9 19 8.6 11.1 5.3 10.8 5.1 <0.20 µmol/day Epinephrine <28 <31 <13 <18 29 <24 <24 <20 <160 nmol/day Norepinephrine 818 426 190 752 1007 574 766 471 89-470 nmol/day Dopamine 3.9 2.1 1 1.6 2.2 1.6 2.4 2.3 0.4–3.3 µmol/day Creatinine 24.1 9.9 12.8 16.7 12.3 16.9 11.7 7-18 nmol/day * On amitriptyline for headaches; ** Off amitriptyline, on beta blocker; *** Off amitriptyline and beta blocker Bold values represent lab results outside the normal limits. 24-h urine catecholamine and metanephrine results prior to OSA treatment. The patient underwent a left adrenalectomy in July 2010. * On amitriptyline for headaches; ** Off amitriptyline, on beta blocker; *** Off amitriptyline and beta blocker Bold values represent lab results outside the normal limits.